Robust Construction of Supersmall Zwitterionic Micelles Based on Hyperbranched Polycarbonates Mediates High Tumor Accumulation

Abstract

Despite the numerous advantages of nanomedicines, their therapeutic efficacy is hampered by biological barriers, including fast in vivo clearance, poor tumor accumulation, inefficient penetration, and cellular uptake. Herein, cross-linked supersmall micelles based on zwitterionic hyperbranched polycarbonates can overcome these challenges for efficiently targeted drug delivery. Biodegradable acryloyl/zwitterion-functionalized hyperbranched polycarbonates are synthesized by a one-pot sequential reaction of Michael-type addition and ring-opening polymerization, followed by controlled modification with carboxybetaine thiol. Cross-linked supersmall zwitterionic micelles (X-CBMs) are readily prepared by straightforward self-assembly and UV cross-linking. X-CBMs exhibit prolonged blood circulation because of their cross-linked structure and zwitterion decoration, which resist protein corona formation and facilitate escaping RES recognition. Combined with the advantage of supersmall size (7.0 nm), X-CBMs mediate high tumor accumulation and deep penetration, which significantly enhance the targeted antitumor outcome against the 4T1 tumor model by administration of the paclitaxel (PTX) formulation (X-CBM@PTX).

Cascade-Catalyzed Nanogel for Amplifying Starvation Therapy by Nitric Oxide-Mediated Hypoxia Alleviation

“…Acryloyl cyclic-carbonate (AC) monomer was synthesized according to our previous method. 43 Bicyclo [6.1.0] non-4-yn-9-ylmethanol (BCN) was successfully synthesized according to the method reported in the literature. 44 Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum (FBS), and trypsin-ethylene diamine tetraacetic acid (EDTA) solution were purchased from Gibco (Waltham).…”

“…NHS-functionalized cyanine-5 was purchased from Xi’an Ruixi Biological Technology Co., Ltd. (Xi’an, China). Acryloyl cyclic-carbonate (AC) monomer was synthesized according to our previous method . Bicyclo [6.1.0] non-4-yn-9-ylmethanol (BCN) was successfully synthesized according to the method reported in the literature .…”

Biodegradable zwitterionic polymers as PEG alternatives for drug delivery

“…Hyperbranched ZPs need to possess sufficient side-chain zwitterions to gain watersolubility. 66 Biodegradable ZP-based crosslinked materials have also been reported. These crosslinked materials possess three-dimensional covalent network structures; therefore, relative to non-crosslinked materials, they have improved stability against environmental changes.…”

“…When cyclic monomers are modified with initiator functionalities, the resulting inimers can be utilized to prepare hyperbranched biodegradable polymers. 66 Biodegradable dendrimers are generally prepared through divergent or convergent synthesis using specifically designed reactants to contain or form biodegradable in-chain functional groups. Terminal functionalities of dendrimers depend on the reactants and chemistries used in the last step.…”

“…Hyperbranched polymers also have branch‐on‐branch structures, but they have less branching density and terminal groups than dendrimers. Hyperbranched ZPs need to possess sufficient side‐chain zwitterions to gain water‐solubility 66 …”